EA011716B1 - Composition comprising ornithine and phenylacetate or phenylbutyrate for treating hepatic encephalopathy - Google Patents

Abstract

The present invention relates to use of ornithine in the manufacture of a medicament for use in combination with at least one of phenylacetate and phenylbutyrate for preventing or treating liver decompensation or hepatic encephalopathy. The invention also relates to use of at least one of phenylacetate and phenylbutyrate in the manufacture of a medicament for use in combination with ornithine for preventing or treating liver decompensation or hepatic encephalopathy.

Description

The present invention relates to the prevention or treatment of decompensated liver or hepatic encephalopathy.

Description of the prior art

Chronic liver disease is characterized by gradual destruction of liver tissue over time, with the result that healthy and regenerating liver tissue is slowly replaced by connective and necrotic tissue. This process is known as cirrhosis. Normal liver function is impaired, and scar tissue causes a progressive decrease in blood flow through the liver. As the normal, regenerating liver tissue is lost, the efficient processing of nutrients, hormones, drugs and toxins stops.

Termination of effective processing can lead to the appearance of symptoms, including abnormal clearance of proteins absorbed through the intestinal tract, leading to the accumulation of ammonia; abnormal excretion leading to accumulation of bilirubin in the blood, causing jaundice; increased sinusoidal pressure leading to fluid accumulation in the abdominal cavity (ascites); and portal hypertension (and portosystemic shunting), in which the scar liver tissue acts as a barrier to blood flow, leading to an increase in portal blood pressure and varicose veins of the esophagus.

Patients with chronic liver disease may be in a fairly stable clinical condition, and they may show some symptoms or symptoms may be absent. However, these patients have a risk of sharp deterioration, which can lead to the development of liver failure along with chronic liver failure. This transition from the “compensated” state, when the liver is able to function, albeit at a reduced level, to the “decompensated” state, when the hepatic function becomes untenable, includes the effect of accelerating events. Accelerating symptoms associated with chronic liver disease include gastrointestinal bleeding, infection (sepsis), portal vein thrombosis, and dehydration.

For example, 50% of patients with cirrhosis have varicose veins of the esophagus, and in a third of patients within two years after diagnosis, the esophageal varices of the varicose veins rupture, which causes gastrointestinal bleeding (Stasé (1992) Sade 511 S11n ΝοΠίι At 21 : 149-161). Bleeding from the upper gastrointestinal tract is known to increase susceptibility to life-threatening complications, such as bacterial peritonitis, sepsis, renal failure, and hepatic encephalopathy (Tegap et al. (1997) Clinic 112: 473-482; Saghep e A1) . (1985) Br 1 8gd 72: 91-95; RaiteN e! A1. (1996) Nera! O1od 24: 802-806; B1e1s11peg e! A1. (1986) Vg 1 8shd 73: 724-726), leading to deaths in approximately 30% of patients, despite adequate control of bleeding (Stasé, 1992, see above).

Hepatic encephalopathy (NOT, PE) is a complex neuropsychiatric disorder that occurs in various clinical situations, such as acute or chronic liver disease and spontaneous portosystemic venous bypass surgery. In the early stages of hepatic encephalopathy, small mental changes occur, such as decreased concentration, confusion and disorientation. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling (brain edema) and death. In the case of patients who develop PE as a result of chronic liver disease, the onset of PE is often the result of a clinically accelerating phenomenon, such as gastrointestinal bleeding, sepsis (infection), portal vein thrombosis or dehydration.

Gastrointestinal bleeding and portosystemic shunting allows toxic substances that are usually metabolized by the liver to enter the systemic circulation and pass through the blood-brain barrier, which has direct or indirect neurotoxic effects on the central nervous system. The accumulation of ammonia is believed to play an important role in the progression of hepatic encephalopathy and multiple organ failure (respiratory failure, cardiovascular failure, renal failure). In addition to the accumulation of ammonia, septicemia (or bacterial peritonitis), which develops soon after gastrointestinal bleeding, is also likely to be a factor contributing to the development of hepatic encephalopathy.

Then, hepatic decompensation can lead to multiple organ failure and hepatic encephalopathy. In the early stages of hepatic encephalopathy, mental changes occur, such as poor concentration or inability to build simple objects. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain edema, and death.

The prognosis for patients with chronic liver disease is difficult to assess, because this condition has many causes. Preventive measures to minimize the progression of the compensated state to the decompensated state include the elimination of exposure to additional pathogenic agents that will worsen the condition, such as total abstinence from alcohol and vaccination against hepatitis A and B.

- 1 011716

However, after the onset of hepatic decompensation, the likelihood of a favorable prognosis is reduced, and liver transplantation is the only treatment that can prolong life. Since it is liver decompensation that leads to a decrease in life expectancy, preventing the occurrence of hepatic decompensation is very desirable.

Routine treatment of patients with hepatic encephalopathy includes strategies to reduce the concentration of ammonia. They include limiting protein intake in the diet; administration of lactulose, ornithine-b-aspartate (BOCA) or sodium benzoate and cleansing enemas.

A brief description of the invention

The present invention relates to the use of ornithine and at least one of phenylacetate and phenylbutyrate for the treatment of hepatic decompensation or hepatic encephalopathy (PE) in patients. Isoleucine can also be administered to patients who, in addition, have isoleucine deficiency, which can be attributed to, for example, gastrointestinal bleeding. Accordingly, the invention relates to:

the use of ornithine for the manufacture of a medicament for use in combination with at least one of phenylacetate and phenylbutyrate for the prevention or treatment of hepatic decompensation or hepatic encephalopathy;

the use of at least one of phenylacetate and phenylbutyrate for the manufacture of a medicine for use in combination with ornithine for the prevention or treatment of hepatic decompensation or hepatic encephalopathy;

the use of ornithine and at least one of phenylacetate and phenylbutyrate for the manufacture of a medicament for the prevention or treatment of hepatic decompensation or hepatic encephalopathy;

products containing ornithine and at least one of phenylacetate and phenylbutyrate, for simultaneous, separate or sequential use for the prevention or treatment of hepatic decompensation or hepatic encephalopathy;

a pharmaceutical composition containing ornithine and at least one of phenylacetate and phenylbutyrate;

an agent for the prevention or treatment of hepatic decompensation or hepatic encephalopathy, containing ornithine and at least one of phenylacetate and phenylbutyrate; and a method of treating a patient with hepatic decompensation or hepatic encephalopathy, or at risk of developing them, wherein the method comprises administering to said patient an effective amount of ornithine and at least one of phenylacetate and phenyl butyrate.

Brief Description of the Drawings

FIG. 1 shows that neutrophil function is impaired in patients with cirrhosis and worsens with increasing severity of hepatic disease.

FIG. 2 shows that ammonia reduces neutrophil phagocytosis.

FIG. 3 shows that ammonia reduces neutrophil chemotaxis.

FIG. 4 shows that the effect of ammonia on phagocytosis of neutrophils can be eliminated by therapeutic interventions.

FIG. 5 shows that simulated gastrointestinal bleeding reduces neutrophil chemotaxis, which can be partially eliminated by the introduction of isoleucine.

FIG. 6 shows that simulated bleeding reduces protein synthesis and inadequately stimulates isoleucine oxidation.

FIG. 7 shows that the introduction of isoleucine during simulated bleeding reduces protein synthesis, but does not reduce the concentration of ammonia.

FIG. 8 shows that the introduction of LOBA reduces the concentration of ammonia, but provides the possibility of the regeneration of ammonia.

FIG. 9 shows that active removal of glutamine prevents the secondary rise in ammonia concentration.

FIG. 10 shows that phenylacetate binds glutamine to produce a cleaved compound and prevents a secondary rise in ammonia concentration.

FIG. 11 shows the effects of ornithine and phenylbutyrate on ammonia levels in patients with advanced cirrhosis.

FIG. 12 shows the effects of ornithine and phenylbutyrate on glutamine levels in patients with advanced cirrhosis.

FIG. 13 shows the mental changes in patients receiving placebo, ornithine (O), phenylbutyrate (P) or O + P.

FIG. 14 shows the effects of ornithine, phenylbutyrate and isoleucine on ammonia levels in patients with advanced cirrhosis.

FIG. 15 shows the effects of ornithine, phenylbutyrate and isoleucine on glutamine levels in patients with advanced cirrhosis.

FIG. 16 shows the effects of ornithine, phenylbutyrate and isoleucine on glycine levels in patients

- 2 011716 ents with advanced cirrhosis.

FIG. Figure 17 shows the effects of ornithine, phenylbutyrate, and isoleucine on isoleucine levels in patients with advanced cirrhosis.

FIG. 18 shows the effects of ornithine, phenylbutyrate and isoleucine on ornithine levels in patients with advanced cirrhosis.

FIG. 19 shows the effect of ornithine and phenylbutyrate on the ammonia content in arterial blood in the bile duct ligation model in rats.

FIG. 20 shows the effect of ornithine and phenylbutyrate on plasma ornithine content in the bile duct ligation model in rats.

FIG. Figure 21 shows the effect of ornithine, phenylbutyrate, and isoleucine on the ammonia content in arterial blood plasma on the model of acute liver failure with elevated blood ammonia in rats.

FIG. 22 shows a weakened increase in the ammonia content in arterial blood under the influence of treatment with ornithine and phenylbutyrate on the model of acute liver failure as a result of liver devascularization in rats.

FIG. 23 shows that ammonia is captured from the blood by the muscles in animals treated with O and PR (samples were taken from the femoral artery vein). In contrast, animals treated with placebo and one P showed an increase in ammonia production by muscles.

FIG. 24 shows that ammonia is produced by the intestines in all animals, with the exception of animals treated with PR (samples were taken from the arteries of internal organs, outflow from which is carried out through the portal vein).

FIG. 25 shows that muscle release of glutamine increases under the influence of O, but not P, used separately. The treatment of ER caused a markedly greater release of muscle glutamine (by capturing, by means of this, ammonia as glutamine in the muscles).

FIG. 26 shows that the uptake of glutamine in the intestine is enhanced by O, but the PR decreases (through this, reducing the formation of ammonia in the intestine).

FIG. 27 shows that ornithine levels in arterial blood increase in two animals (in groups receiving one O and PR) to which it was administered.

FIG. 28 shows that arterial blood glutamine levels increase with O treatment, but to a lesser extent with OR treatment.

FIG. 29 shows that the combination of OP prevents the increase in the content of ammonia-causing amino acid glycine.

FIG. 30 shows that one ornithine causes an increase in the water content in the brain, phenylacetate causes a slight increase in the water content in the brain, while the combination of these agents causes a significant decrease in the water content in the brain (% of control).

Detailed Description of the Invention

Throughout the present description and the accompanying claims, the words "comprise" and "include" and variations such as "contain", "includes" and "including" should be interpreted as "including". That is, these words are intended to express the possible inclusion of other elements or integers that are not specifically indicated, if the context allows.

The present invention relates to the early treatment of patients with liver disease before the development of hepatic decompensation and, thus, before the occurrence of hepatic encephalopathy, to prevent or delay the onset of hepatic decompensation. Alternatively, the present invention relates to the treatment of hepatic encephalopathy by effectively reducing the concentration of ammonia and maintaining the function of neutrophils.

Individuals to be treated.

The present invention relates to the prevention or treatment of hepatic decompensation or hepatic encephalopathy. Thus, the liver of an individual may be in a compensated state. An individual may have chronic liver disease. An individual may have cirrhosis of the liver. An individual may have acute liver failure. The individual to be treated may have hepatic encephalopathy.

Onset of both acute and chronic liver disease may be caused by a xenobiotic cause. For example, an individual may be in contact with a chemical, drug, or some other agent that causes liver damage. An individual may have a reaction to an over-the-counter, prescribed or “wellness” drug that causes liver damage. An individual could take Be / Yip ™ (troglitazone; Ragke-Eau18), Zekope ™ (nefazodone; Br181o1-Mueg8 Zs. | Shb) or other drugs that are believed to cause liver damage. An individual may be a person who has an overdose of a particular drug or who has exceeded the recommended dosage of the drug that could cause liver damage. For example, an individual could take an excess dose of paracetamol. An individual could be in contact with chemicals that could cause liver damage, such as, for example, at the site of his work. For example, an individual could contact such

- 3 011716 chemicals in industrial or agricultural environment. An individual could eat plants that contain compounds capable of causing liver damage, in particular, this could be the case if the individual is an animal, such as a herbivore. For example, an individual could eat a plant containing a pyrrolizidine alkaloid, such as a ground spider. An individual could be exposed to environmental toxins that are thought to cause liver disease.

Toxic liver damage associated with drug intake accounts for more than 50% of all cases of acute liver disease (acute liver failure). The toxic effect of acetaminophen (also known as paracetamol and Ν-acetyl-p-aminophenol) is the most common cause of acute liver failure in the United States and the United Kingdom. Persons who use moderate and large doses of alcohol for a long time, when taking acetaminophen in therapeutic or moderately excessive doses, have a risk of severe liver damage and, possibly, acute liver failure. Alcohol potentiates the toxic effects of acetaminophen. Idiosyncratic drug toxicity also contributes to the development of acute liver failure. Idiosyncratic drug toxicity is considered to be a hypersensitivity reaction in which an individual responds to a drug in a pharmacologically abnormal manner. Such an abnormal reaction can lead to acute liver failure.

Acute liver failure or chronic liver disease can be caused by infection by a pathogen. For example, liver disease can be caused by a viral infection. In particular, an individual may be infected or has been infected by a virus that causes hepatitis. An individual may have chronic viral hepatitis. The virus may, for example, be a hepatitis B, C or Ό virus. In some cases, and in particular when an individual has viral hepatitis, the individual may also be infected with HIV-Ι or II. An individual may have AIDS. It is possible that the individual was or is infected with other organisms that cause liver disease, and in particular those that are present in the liver during some stage of their life cycle. For example, an individual may have or had a hepatic fluke.

An individual may have a hereditary disease that causes or increases the risk of chronic liver disease. For example, an individual may have one of the following diseases: liver hemochromatosis, Wilson's disease, or α-1-antitrypsin deficiency. An individual may have a hereditary disorder that causes some type of hepatic structural or functional abnormality that increases the likelihood of liver fibrosis. An individual may be genetically predisposed to develop an autoimmune disorder that damages the liver and, therefore, that can contribute to the development of liver fibrosis.

Chronic liver disease can be caused by alcohol. The men or women to be treated may suffer or suffer from alcoholism. He or she may consume or consume an average of 50 or more units of alcohol per week, 60 or more units of alcohol per week, 75 or more units of alcohol per week and even 100 or more units of alcohol per week. A man or a woman can consume or consume on average up to 100 units of alcohol per week, up to 150 units of alcohol per week, and even up to 200 units of alcohol per week. Measuring one unit of alcohol differs from country to country. Here, one unit is equal to 8 g of ethanol in accordance with the UK standard.

A man or woman could consume these levels of alcohol for 5 years or more, 10 years or more, 15 years or more, or 20 years or more. An individual could consume such levels of alcohol for a period of up to 10 years, up to 20 years, up to 30 years, and even up to 40 years. In the case of alcohol-induced cirrhosis, the age of an individual may be, for example, 25 years or more, 35 years or more, 45 years or more, and even more than 60 years.

An individual may be male or female. A woman may be more susceptible to the adverse effects of alcohol than a man. A woman's chronic alcoholic liver disease can develop into a shorter timeframe and from less alcohol than a man. It seems that there is not only one factor that can explain the increased susceptibility to alcoholic liver damage in women, but the influence of hormones on alcohol metabolism may play an important role.

In other embodiments, the individual may have one or more of a number of other conditions that are known to cause liver damage such as, for example, primary biliary cirrhosis, autoimmune chronic active hepatitis, and / or schistosomiasis (parasitic infection). An individual may have or has had a bile duct blockage. In some cases, the underlying cause of chronic liver disease may not be known. For example, an individual may be diagnosed with cryptogenic cirrhosis. In one embodiment, the individual may have a suspicion of any of the conditions listed here.

Methods for the diagnosis of chronic liver disease, acute liver failure and hepatic encephalopathy are well known in the field and, in particular, to clinicians and veterinarians in the field. Preferably, the diagnosis of liver disease and hepatic encephalopathy will be

- 4 011716 delivered, for example, by a doctor or veterinarian. An individual may have one or more symptoms associated with liver disease, such as one or more of jaundice, ascites, skin changes, fluid retention, nail changes, easy bruising, nasal bleeding, esophageal varices, and increase in mammary glands. An individual may show exhaustion, fatigue, loss of appetite, nausea, weakness and / or loss of body weight. The individual may also show one or more symptoms associated with hepatic encephalopathy, such as one or more of confused consciousness, disorientation, dementia, stupor, coma, brain edema, multiple organ failure (respiratory failure, cardiovascular failure or renal failure), muscle tightness rigidity, convulsions or speech disorders. The individual to be treated can take or have taken other drugs to treat liver disease. The individual to be treated may have a risk of developing hepatic encephalopathy.

Hepatic disease could be confirmed or confirmed by physical examination, including techniques such as ultrasound. Liver biopsies can be taken to control the growth of fibrosis, the appearance of necrotic cells, cell degeneration and / or inflammation and other characteristic signs of liver disease. An individual could have been evaluated for liver function to determine if the individual is impaired. The nature and cause of the hepatic disease can be characterized. Any history of contact with pathogenic agents of hepatic disease can be determined.

The individual to be treated may have a risk of episodes of hepatic encephalopathy, for example in patients who are awaiting liver transplants, surgical patients and / or patients with portal hypertension. An individual with a risk of hepatic encephalopathy is an individual who has not suffered any episodes of hepatic encephalopathy or has not suffered from any episode of hepatic encephalopathy for an extended period of time (approximately 12 weeks or longer), but has a disorder or medical condition that creates an episode risk hepatic encephalopathy. An episode of hepatic encephalopathy is a condition characterized by the presence of brain dysfunction in patients with liver disease or dysfunction. There is a wide range of mental disorders in hepatic encephalopathy, which is in the range of minimal, in which the main effects are a decrease in the quality of life, to obvious, which lead to coma and, ultimately, to death.

Scoring systems can be used to assess the severity of liver disease and hepatic encephalopathy, as well as prognosis in individuals. You can use the scoring system Sy1b-Ridy, Ac81 Nauei Sigpa. S1a8do \\ · Sota 8sa1e or a modified scoring system S1i1b-Rid11. Alternatively, a scoring system (APACHE) II can be used. Scores are awarded to parameters including serum bilirubin levels, serum albumin levels, and signs including the presence of ascites or encephalopathy. Individuals to be treated can be classified as Class A, B, or C according to the sc1b-ready scoring system. As a rule, individuals to be treated belong to class C according to the sc1b-ready scoring system.

The man or woman to be treated may be aged, for example, from 25 to 80 years. In one embodiment, the age of the man or woman is from 45 to 70 years. In another embodiment, the age of the man or woman is from 25 to 44 years. In yet another embodiment, the age of the man or woman is over 65 years.

However, the invention can be applied in veterinary medicine. The subject to be treated can be an agricultural animal, such as a cow or a bull, a sheep, a pig, an ox, a goat or a horse, or it can be a domestic animal, such as a dog or a cat. The subject may or may not be an experimental model of liver disease in an animal. The age of the animal can be any, but it will often be a sexually mature, adult animal.

Preparative form.

Amino acids used in the present invention may be pure crystalline amino acids. As a rule, amino acids are presented in the b-form, and not in the Ό-form, or as a mixture of and b. Usually used selected forms of amino acids. For the prevention or treatment of hepatic decompensation or hepatic encephalopathy, you can use any active form of amino acids. A pharmaceutically acceptable form of the amino acid may be used. Amino acids can be used in the form of free amino acids or salts or derivatives of amino acids.

Ornithine may be in the form of a pure crystalline amino acid. Ornithine is usually presented in the b-form, and not in the Ό-form, or as a mixture of and b. Commonly used forms of ornithine are used. You can use any active form of ornithine or a pharmaceutically acceptable form of ornithine. Ornithine can be used in the form of a free amino acid or a salt or derivative of an amino acid.

Ornithine is usually used as a single monomeric amino acid. Ornithine can be used in salt form, for example, ornithine hydrochloride can be used. Ornithine may be in the form of a physiologically acceptable salt in the free form. Therefore ornithine or ornithine salt

- 5 011716 are usually not chemically bound or covalently bonded to any other agent.

Ornithine derivatives may be used. For example, ornithine keto or hydroxy-analogs can be administered as sodium or calcium salts. Ornithine keto acids include ornithine ketoglutarate, ornithine ketoleucine, and ornithine ketovaline. Ornithine salts or derivatives can be used instead of or in addition to free ornithine.

At least one of phenylacetate and phenylbutyrate can be used. The phenylacetate and / or phenylbutyrate may be in the form of a physiologically acceptable salt, such as an alkali metal salt or alkaline earth metal salt. This salt may be sodium phenylacetate or sodium phenylbutyrate. The salt form of phenylacetate and phenylbutyrate may be in free form. Therefore, the phenylacetate and phenylbutyrate or the phenylacetate salt and the phenylbutyrate salt are usually not chemically bound or covalently bonded to any other agent.

Optionally, isoleucine is used. Isoleucine may be in the form of a pure crystalline amino acid. As a rule, isoleucine is presented in the b-form, and not in the Ό-form, or as a mixture of and b. Usually used isolated forms of isoleucine. You can use any active form of isoleucine or a pharmaceutically acceptable form of isoleucine. Isoleucine can be used in the form of a free amino acid or a salt or derivative of an amino acid.

Normally, isoleucine is used as the only monomeric amino acid. Isoleucine can be used in the form of a salt, for example, isoleucine hydrochloride can be used. Isoleucine may be in the form of a physiologically acceptable salt in the free form. Therefore, isoleucine or isoleucine salt is usually not chemically bound or covalently bonded to any other agent.

Pharmaceutical compositions.

Ornithine and phenylacetate and / or phenylbutyrate are usually formulated for administration with a pharmaceutically acceptable carrier or diluent. Thus, ornithine and phenylacetate and / or phenylbutyrate can be formulated as a drug with standard pharmaceutically acceptable carrier (s) and / or excipient (excipients), which is a common procedure in the pharmaceutical field. The exact nature of the formulation will depend on several factors, including the desired route of administration. Usually, ornithine and phenylacetate and / or phenylbutyrate are formulated for oral, intravenous, intragastric, intravascular, or intraperitoneal administration.

The pharmaceutical carrier or diluent may, for example, be an isotonic solution, such as physiological saline. Solid oral forms may contain, along with the active compound, for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binders, such as starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose, or polyvinylpyrrolidone; disintegrating agents, for example starch, alginic acid, alginates or sodium starch glycolate; foaming mixtures; colorants; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and, as a rule, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations can be manufactured in a known manner, for example, by methods of mixing, granulating, tabletting, sugar coating or film coating.

Liquid dispersions for oral administration may be syrups, emulsions or suspensions. Syrups may contain as carriers, for example, sucrose or sucrose with glycerin, and / or mannitol, and / or sorbitol.

Suspensions and emulsions may contain as carrier, for example, a natural resin, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. Suspensions or solutions for intramuscular injections may contain, along with ornithine and at least one of phenylacetate and phenylbutyrate, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.

The medicaments of the invention may include ornithine as the sole amino acid component. The medicaments of the invention may include ornithine and isoleucine as the only amino acid components. The drug may consist essentially of ornithine and at least one of phenylacetate and phenylbutyrate. The drug may consist essentially of ornithine, isoleucine and at least one of phenylacetate and phenylbutyrate.

The drug may consist essentially of ornithine, phenylacetate and / or phenylbutyrate, and a pharmaceutically acceptable carrier. Therefore, such a drug does not substantially contain another amino acid in addition to ornithine. The drug may consist essentially of ornithine, isoleucine, phenylacetate and / or phenylbutyrate, and a pharmaceutically acceptable carrier. Therefore, such a drug does not substantially contain another amino acid in addition to ornithine and isoleucine.

- 6 011716

Phenylacetate may be present in an amount of from 5 to 100 wt.%, For example from 10 to 50 wt.% Or from 20 to 40 wt.%, Ornithine. Phenylbutyrate may be present in an amount of from 5 to 100%, for example from 10 to 50 wt.% Or from 20 to 40 wt.%, Ornithine.

However, the drug may include free aspartate, glutamate or arginine in a non-peptide form, usually in small amounts. As a rule, the amount by weight of aspartate, glutamate or arginine does not exceed the amount by weight of ornithine. By minor amount is meant that the amount by mass of aspartate, glutamate or arginine or a combination of these amino acids does not exceed 20% by weight of ornithine. Therefore, the drug may essentially not include aspartate. In one embodiment, the composition does not include aspartate, glutamate or arginine. Trace amounts of aspartate, glutamate or arginine may be present in the composition. By trace amounts, it is meant that the amount by mass of aspartate, glutamate or arginine, or a combination of these amino acids does not exceed 1% by weight of ornithine. Preferably, the amount by weight of aspartate, glutamate or arginine does not exceed 0.5 wt.% Ornithine.

In another embodiment, the composition may include another amino acid in a non-peptide form, usually in the form of a free amino acid or its physiologically acceptable salt in a free form. The amount of these other amino acids generally does not exceed the amount by weight of ornithine. For example, other amino acids may be present in an amount by weight up to 20% by weight, for example from 5 to 20% by weight, of ornithine. Such other amino acids that may be present in the composition include non-essential and non-essential amino acids. The composition may include other branched chain amino acids (BCAAs). BCAAs include isoleucine, valine and leucine. Thus, the composition according to the invention may additionally include isoleucine and / or valine and / or leucine.

Treatment.

Ornithine and at least one of phenylacetate and phenylbutyrate are administered in combination to an individual to prevent or delay the onset of hepatic decompensation or hepatic encephalopathy. Thus, ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to improve the condition of the individual, for example, an individual suffering from chronic liver disease, after an accelerating phenomenon. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to alleviate symptoms in an individual, such as symptoms associated with chronic liver disease in an individual, after an accelerating event. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to counter or delay the onset of hepatic decompensation or hepatic encephalopathy.

Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to an individual to treat hepatic encephalopathy. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to improve the condition of a patient suffering from hepatic encephalopathy. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to alleviate the symptoms associated with hepatic encephalopathy. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to combat hepatic encephalopathy. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to prevent the initial episode of hepatic encephalopathy in an individual at risk of episodes of hepatic encephalopathy. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to reduce the severity of the initial episode of hepatic encephalopathy in an individual at risk of episodes of hepatic encephalopathy. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination to delay the initial episode of hepatic encephalopathy in an individual at risk of episodes of hepatic encephalopathy.

The development of hepatic decompensation and hepatic encephalopathy includes “accelerating events” (or “acute attacks”). Such accelerating effects include gastrointestinal bleeding, infection (sepsis), portal vein thrombosis, and dehydration. The onset of such an acute attack can lead to hospitalization. A patient may suffer from one of these acute attacks or a combination of these acute attacks.

An individual who has or is suspected of having an acute attack is treated in accordance with the invention with ornithine and phenylacetate and / or phenylbutyrate in combination to prevent the progression of liver damage to a decompensated state. Therefore, the treatment according to the invention can prevent the medical consequences of hepatic decompensation, such as hepatic encephalopathy. Ornithine and phenylacetate and / or phenylbutyrate can be used to preserve hepatic function. Thus, the use of ornithine and phenylacetate and / or phenylbutyrate can prolong the life of a patient with liver disease. In one embodiment, the metabolic effects of gastrointestinal bleeding are prevented, such as increased blood ammonia, reduced isoleucine levels in the blood, and reduced protein synthesis during the post-bleeding period.

Usually, treatment of individuals can be started as early as possible after the onset or suspected.

- 7 011716 mio beginning of the accelerating phenomenon (acute attack). Preferably, treatment of the individual begins before repeated acute attacks. More preferably, treatment of the individual begins after the first acute attack.

Treatment is usually carried out soon after the onset of an acute attack. Treatment may begin after a symptom (s) of an acute attack or a suspected acute attack is identified by a physician, such as a doctor, medical assistant or nurse. Treatment may begin after an individual is hospitalized. Thus, treatment can begin within 6 hours, within 3 hours, within 2 hours, or within 1 hour after identifying the symptom (s) of an acute attack or a suspected acute attack. Therefore, treatment of an individual can begin 1–48 hours, for example, 1-36 hours or 124 hours after the symptom (s) of an acute attack or a suspected acute attack is detected.

Treatment may occur for up to 8 weeks, for example, up to 6 weeks, up to 4 weeks, or up to 2 weeks after the symptom (s) of an acute attack or a suspected acute attack is detected. Therefore, treatment may occur during the period up to 48 hours, for example, up to 36 hours, or up to 24 hours after the symptom (s) of an acute attack or a suspected acute attack is detected. Treatment usually takes place until the time when recovery from an acute accelerating phenomenon is apparent.

Individuals are treated with ornithine and phenylacetate and / or phenyl butyrate. Ornithine and at least one of phenylacetate and phenylbutyrate can be administered in combination as a single drug or as two or three different drugs. When ornithine and at least one of phenylacetate and phenylbutyrate are to be administered as a combination drug, the combination can be obtained immediately before administration, or it can be stored as a combination drug.

When ornithine and phenylacetate and / or phenylbutyrate are to be administered separately, the drugs can be administered simultaneously or sequentially over a period of time. Two or three separate drugs can be administered over a period of time.

When two drugs are administered, ornithine can be administered first, followed by the introduction of phenylacetate and phenylbutyrate, phenylacetate or phenylbutyrate. Alternatively, phenylacetate and phenylbutyrate, phenylacetate or phenylbutyrate can be added first followed by the introduction of ornithine. In another embodiment, a combination of ornithine and phenylacetate can be administered first followed by the introduction of phenylbutyrate. Alternatively, a combination of ornithine and phenylbutyrate can be administered first followed by the administration of phenylacetate. In another embodiment, phenylacetate may be administered first followed by the administration of a combination of ornithine and phenylbutyrate. Alternatively, phenylbutyrate can be administered first followed by the introduction of a combination of ornithine and phenylacetate.

When three drugs are administered, ornithine, phenylacetate and phenyl butyrate are administered at different times. Ornithine can be administered first, second or third. When ornithine is first administered, phenylacetate or phenylbutyrate can be added second followed by the introduction of phenylbutyrate or phenylacetate. When ornithine is administered second, phenylacetate or phenylbutyrate is first introduced, and phenylbutyrate or phenylacetate is introduced third. When ornithine is administered third, phenylacetate or phenylbutyrate is first introduced, and phenylbutyrate or phenylacetate is administered second.

The second drug can be administered at intervals up to 5 hours, for example, up to 2 hours or up to 1 hour after the administration of the first drug. Thus, the second drug can be administered at intervals of from 15 minutes to 5 hours, for example, from 30 minutes to 4 hours, or from 1 to 3 hours after the administration of the first drug.

The third drug can be administered at intervals up to 5 hours, for example, up to 2 hours or up to 1 hour after the administration of the second drug. Thus, the third drug can be administered at intervals of from 15 minutes to 5 hours, for example, from 30 minutes to 4 hours, or from 1 to 3 hours after the administration of the second drug.

The medicaments of the invention may be administered in the same region or in different regions. The medicaments of the invention can be administered in the same way or in different ways. The drug of the invention may be administered by any suitable route. Preferably, it is administered by the oral, intravenous, intragastric, intraperitoneal or intravascular route. For example, when ornithine and at least one of phenylacetate and phenylbutyrate are administered separately, they can all be administered orally, or they can be administered intravenously, ornithine can be administered orally, and phenylacetate and / or phenylbutyrate can be administered intravenously, or phenylacetate and / or phenylbutyrate can be administered orally, and ornithine can be administered intravenously.

Therapeutically effective amounts of ornithine, phenylacetate and / or phenylbutyrate and an optional isoleucine are administered to the individual. Doses of ornithine, phenylacetate and / or phenylbutyrate and isoleucine can be determined according to various parameters, such as age, body weight, and the condition of the individual being treated; the type and severity of liver disease; routes of administration; and the required treatment regimen.

Depending on these parameters, the usual dose of ornithine, phenylacetate and / or phenylbutyrate or

- 8 011716 isoleucine is from 0.02 to 1.25, for example from 0.1 to 0.5 g / kg body weight. Consequently, the dosage of ornithine, phenylacetate and / or phenylbutyrate or isoleucine can be from 1 to 50 g, for example, from 5 to 30 g. The dosage of ornithine can be from 10 to 30 g. The dosage of isoleucine can be from 5 to 15 g. Ornithine and phenylacetate / phenylbutyrate can be entered in a mass ratio of from 10: 1 to 1:10, for example from 5: 1 to 1: 5 or from 2: 1 to 1: 2 or about 1: 1. The doctor will be able to determine the required dosage of ornithine and phenylacetate or phenylbutyrate and an optional isoleucine for any particular individual.

You can enter a single dose of ornithine and a single dose of phenylacetate and / or phenylbutyrate. Optionally, you can also enter a single dose of isoleucine. Alternatively, multiple doses may be administered, for example, 2, 3, 4 or 5 doses of ornithine and / or phenyl acetate and / or phenyl butyrate and / or an optional isoleucine. Such multiple doses can be administered within 1 month or 2 weeks or 1 week. In another embodiment, a single dose or multiple doses, for example, 2, 3, 4 or 5 doses of ornithine and / or phenylacetate and / or phenylbutyrate, can be administered daily.

As noted above, other amino acids can be administered to the individual. Each such or another amino acid can be administered in the same drug as ornithine and / or phenylacetate and / or phenyl butyrate, or it can be administered separately. When administered separately, each such or another amino acid can be administered simultaneously with the administration of ornithine and / or phenylacetate and / or phenylbutyrate, or at another time, for example, before administration or at intervals up to 5 hours, up to 2 hours, or up to 1 hour after their administration. Each such or another amino acid is usually administered orally or intravenously.

The individual is administered a therapeutically effective amount of each such or another amino acid. The dose will depend on various parameters, such as the parameters noted above for ornithine, phenylacetate and phenylbutyrate. The usual dose of each such or other amino acid is from 0.02 to 1.25, for example, from 0.1 to 0.5 g / kg body weight. Therefore, the dosage of each such or another amino acid can be from 1 to 50 g, for example from 5 to 30 g.

You can enter a single dose of each such or other amino acids. Alternatively, multiple doses may be administered, for example 2, 3, 4 or 5 doses. Such multiple doses can be administered within 1 month or 2 weeks or 1 week. In another embodiment, a single dose or multiple doses, for example 2, 3, 4 or 5 doses, can be administered daily.

The following examples illustrate the invention.

Example 1. The function of neutrophils is altered in patients with cirrhosis and worsens with increasing severity of liver disease.

Methods for measuring neutrophil phagocytosis and oxidative burst.

Phagocytic test: Heparinized whole blood was incubated with opsonized, ITS-labeled (fluorescein-isothiocyanate) E. Soi and SI16. The cells were then analyzed by flow cytometry (EAC8cap VssYup O | sk | p5op). passed through a direct or side scatterer and then evaluated on the basis of the expression of fluorochrome B-phycoerythrin (PE) [Types, Magnesé, Egapsé] to identify the SI of 16 positive cells. The population that passed through the diffuser was then assessed for the presence of E1TC-labeled bacteria.

Phagocytic surge: Heparinized whole blood was incubated with a suspension of opsonized E. Soy to stimulate an oxidative burst. A substrate solution was added to determine the conversion of dihydrogen rodamine (ΌΗΒ) 123 to the fluorogenic compound rhodamine (B) 123. The reaction was stopped and fixed before incubation with an antibody against SI16 to identify positive neutrophils. Then, flow cytometry analysis was performed.

Neutrophil Chemotaxis: Neutrophil chemotaxis was measured using a modified Boyden chamber method using interleukin-8 as a chemoattractant to mimic chemokinesis.

Patients and methods.

The applicants studied 30 patients with cirrhosis [alcoholic cirrhosis; average age of 53.2 g (8EM 4.6)] and 20 healthy volunteers. Patients with cirrhosis were divided into patients with introduced alcoholic hepatitis (AH +) and patients with decompensated or compensated liver. Phagotest was used to determine phagocytic ability and a phagocytic surge was used to determine whether cells were able to generate an oxidative burst upon contact with E. soy.

Results.

It was observed that neutrophils from patients with cirrhosis had a significantly reduced ability to phagocytize bacteria. It was also found that in patients with cirrhosis, the ability to respond to the stimulation of neutrophil E.soy was reduced from the point of view of increasing the rate of generation of the oxidative burst (Fig. 1). This decrease in ability correlated with the severity of liver disease, indicating that the more advanced the liver disease stage, the less the ability to react and fight infection.

Example 2. Ammonia reduces the phagocytic ability of neutrophils.

Methods for measuring neutrophil phagocytosis and oxidative burst.

- 9 011716

As in example 1.

Patients and methods.

Blood was taken from healthy volunteers (n = 15) and incubated for 1 h with increasing concentrations of ammonia. The ability of neutrophils to phagocytose bacteria was measured using phagotest and neutrophil chemotaxis assays. In the analysis of neutrophil chemotaxis, 10 ng / ml 1b-8 was used.

Results.

Incubation with increasing concentrations of ammonia showed a significant decrease in neutrophil phagocytosis (Fig. 2), as well as neutrophil chemotaxis (Fig. 3).

Example 3. The effect of ammonia on phagocytosis of neutrophils can be avoided by interventions.

Methods for measuring neutrophil phagocytosis and oxidative burst.

As in example 1.

Patients and methods.

Blood was taken from healthy volunteers (n = 15) and incubated for 1 h with ammonia and selected amino acids. The ability of neutrophils to phagocytose bacteria was measured using phagotest assays.

Results.

It was observed that the decrease in neutrophil phagocytosis caused by ammonia can be partially eliminated by ornithine and glutamine (Fig. 4). However, neutrophil phagocytosis became worse under the influence of co-incubation of ammonia with aspartate, but remained unchanged with b-ornithine-b-aspartate.

Example 4. Simulated gastrointestinal bleeding reduces neutrophil chemotaxis, which can be partially eliminated by the introduction of isoleucine.

Methods

metabolically stable patients [9 men and 1 woman; mean age 49.6 years (8EM 9.1); mean score on Οιίΐά-Ριίβΐι 7.8 (8EM 1,2)] with a confirmed liver biopsy was investigated after fasting overnight before and 2 hours after oral administration of 75 g of an amino acid mixture that mimics a hemoglobin molecule (ΝιιΙΝποίη. Siuk, №1 keg1apj8). Seven other patients [(4 men and 3 women; mean age 51.4 years (8EM 6.7); average score on the scale of Οιί1ά-Ριι§1ι 8.1 (8EM 1,4)) after administration of the mixture of amino acids, intravenous isoleucine over a 2-hour period (isoosmotic solution containing 40 mg / l isoleucine, at a rate of 100 ml / h). In samples of peripheral venous blood, neutrophil chemotaxis was measured (see method in example 1) and plasma ammonia.

Results.

In these patients with cirrhosis, neutrophil chemotaxis was significantly lower compared with age-matched controls (53.3 ± 4.6), and it was significantly reduced after simulated bleeding from 31 (± 4.2) to 8 (± 5.4 a) cells / high power field (p <0.0001) (Fig. 5). The plasma ammonia concentration increased significantly from 75.1 (± 4.2) to 124 (± 8.5) (p <0.001). The change in ammonia concentration was correlated with changes in neutrophil chemotaxis (r = 0.65 and p <0.05). The reduction in neutrophil chemotaxis observed in simulated bleeding was eliminated in a group of patients treated with isoleucine 25.4 (± 6.0) cells / field with a high magnification.

Example 5. Simulated bleeding reduces protein synthesis and inadequately stimulates isoleucine oxidation.

Methods

The study included 5 patients with cirrhosis, starving during the night. A sample of blood and exhaled air samples were taken before the start of the infusion of stable isotopes to measure background enrichment with isotopes. Then the patients received primed constant intravenous infusion of [1- ¹³ C] isoleucine (1 mg / kg bw / h) until the end of the experiment (1 = 480 min).

Results.

FIG. 6 shows the average rate of occurrence of oxidation of isoleucine (\ ¥ L on) and isoleucine in the whole body during the last hour of the infusion of saline (black bars) and amino acids (gray bars) (mean ± 8EM; # represents p <0.05). Bleeding from the upper part of the gastrointestinal tract in patients with cirrhosis resulted in a decrease in the level of isoleucine and a pronounced decrease in protein synthesis throughout the body. The fraction of the current isoleucine used for oxidation did not change after simulated bleeding, despite a marked decrease in the concentration of isoleucine, indicating the occurrence of antagonism against BCAAs.

Example 6. The introduction of isoleucine during simulated bleeding increases protein synthesis, but does not reduce the concentration of ammonia.

Methods

Investigated 16 metabolically stable patients with a confirmed biopsy of liver cirrhosis. Patients were randomized to include either isoleucine (40 mg / l solution; 50 ml / h) or placebo during simulated bleeding for a 4-hour period.

- 10 011716

Protein synthesis (measured using primed continuous infusion of L- [koltsevogo- ² H5] -phenylamine, L- [koltsevogo- ² H4] tyrosine and L- [koltsevogo- ² H _2] tyrosine) and ammonia.

Results.

The results showed that an injection of isoleucine during simulated bleeding in patients with cirrhosis of the liver restores the protein synthesis of the liver and muscles, leading to a pure anabolic state in these organs (Table 1). The concentration of ammonia increased significantly in both groups, but did not significantly differ in the groups treated with isoleucine or placebo (Fig. 7).

Example 7. The accumulation of aspartate after the infusion of b-ornithine-b-aspartate in patients with advanced cirrhosis.

Methods

patients with advanced cirrhosis who were expecting liver transplantation (age: 59 years; 3 men, class C disease according to S1Ib. severe ascites, creatinine 102 mmol / l) were treated with 40 g / day L-ornithine-L-aspartate.

Results.

During the 3-day period, there was a significant and progressive increase in the concentration of aspartate, 5 times the initial value (Table 2).

Table 1

Protein kinetics, determined by using the model Pru in b = 0 h and at the end of the study

Time Synthesis ¹ squirrel R Protein breakdown Rub Clean the remainder R Liver imitated 0 415 ± 120 263 ± 50 152 ± 76 saline bleeding the end 274 ± 250 0.445 108 ± 162 0.366 166 ± 231 0.836 imitated 0 218 ± 37 109 ± 25 98 ± 33 isoleucine bleeding the end 839 ± 221 0.038 157 204 0.412 682 ± 165 0,010 Bottom imitated 0 117 ± 52 137 ± 51 -20 ± 19 limb saline bleeding the end 372 211 0.189 288 ± 175 0.232 87 _: ± 140 0.694 imitated 0 -31 ± 201 196 + 61 -185 ± 152 isoleucine bleeding the end 377 ± 135 0.209 159 ± 100 0.535 261 ± 102 0,005

Data are the mean ± BEM in nmol / kg body weight / min. The final values represent the average values of the final hour of the amino acid infusion. Data on protein synthesis in the liver and kidneys are corrected for hydroxylation (see methods).

Statistics: p-values for the Mapp- У ШShpsu criterion for differences within groups; no statistical differences were found between groups.

table 2

Before the introduction 1st day 2nd day 3rd day Aspartate 72 178 289 354 (µmol / l (11.8) (23.2) (27.1) (31.1)

Example 8. The introduction of LOBA reduces the concentration of ammonia, but allows the ammonia to be regenerated.

Patients and methods.

patients with cirrhosis (age 56 (5,6), 5 men, ABE-6; NOT (hepatic encephalopathy) Grade 2: 4 patients; NOT Grade 3-4: 4 patients) were treated with a ROH infusion (40 g for 8 h ). Blood samples were taken to measure ammonia and glutamine levels.

Results.

The results showed that the introduction of BOBA led to a significant decrease in the concentration of ammonia with a concomitant increase in the concentration of glutamine (Fig. 8). This reduction in ammonia had beneficial effects on the severity of HE. However, when the administration of LOBa was stopped, there was a reactive increase in the levels of circulating ammonia, leading to a recurrence of NO in 3 out of 6 patients whose condition had previously improved.

Example 9. The active removal of glutamine prevents the secondary rise in the concentration of ammonia.

Patients and methods.

patients [age 45 (4.1), 2 men, ABE; in all HE 3, in all 3 NRBs] who underwent prolonged veno-venous hemofiltration (SUUN), were treated with an LoBa infusion (40 g for 8 h). Blood samples were taken to measure ammonia and glutamine levels.

Results.

The results showed that the introduction of BOBA led to a decrease in the concentration of ammonia, but the addition of dialysis prevented a concomitant increase in the concentration of glutamine (Fig. 9). Therefore, the applicants believe that there was a persistent decrease in the concentration of ammonia.

Example 10. Phenylacetate binds glutamine to produce an excreted compound and prevents the secondary rise in ammonia.

Patients and methods.

patients with acute liver failure (5 patients with non-A non-B hepatitis) and severe

- 11 011716 encephalopathies (3-4 degrees) were treated with BOBA and phenylacetate (40 g / day for 8 hours).

Results.

In the combined treatment, there was no significant increase in glutamine concentration, and ammonia levels were reduced (Fig. 10). A reactive increase in ammonia was not observed.

Example 11. The effect of ornithine and phenylbutyrate in patients with hepatic encephalopathy. Patients.

1. Groups - 3 patients per group. Total 12.

2. Inclusion criteria adult patients aged 18-80 years - liver cirrhosis, documented by histology or clinical criteria;

NOT type C - ammonia concentration> 80 mmol / l, informed consent / permission.

3. Exclusion criteria are another concomitant neurological disorder, the use of another specific drug that reduces the level of ammonia, respiratory failure requiring mechanical ventilation and sedative treatment, profuse gastrointestinal bleeding, hypotension requiring the use of inotropic drugs, obvious renal failure (creatinine> 2 mg / dcl), hemodialysis, extracorporal support of the liver, known hypersensitivity to any of the studied drugs, ber amenity

Mental state evaluation.

Determination of the degree of hepatic encephalopathy (criteria HUECH Nauei)

Degree 0 (minimum NOT) normal mental state (one or more quantifiable anomalies during psychometric testing) Grade 1 trivial lack of awareness, euphoria or anxiety shortened attention period disturbed execution of addition Grade 2 lethargy or apathy minimal disorientation in time and place slight personality change inadequate behavior impaired performance of subtraction Grade 3 drowsiness to a state of semi-impairment, but persistence of reaction to verbal stimuli, confused consciousness severe disorientation Grade 4 Coma (lack of response to verbal or pain stimuli)

Methods

The open study included 8 patients with cirrhosis and elevated levels of ammonia in the blood. They were selected according to the severity of the lesion of the liver (see Table 3). They were treated with one of the following regimens for a 3-day period and observations were carried out for 5 days. The study groups were as follows:

(ί) Placebo: 5% dextrose for 4 hours;

(ίί) One ornithine: 20 g in 500 ml, 5% dextrose from 08:00 to 12:00 in the morning;

(ίίί) Phenylbutyrate: 10 g 2 times a day, orally (at 08:00 and at 16:00); and (ίν) Ornithine + phenylbutyrate: 20 g in 500 ml, 5% dextrose from 08:00 to 12:00 in the morning + 10 g 2 times a day, orally (at 08:00 and at 16:00).

Patients were hungry during the night from midnight (00:00 h) to 08:00 h in the morning. They were fed intragastric ration 25 kcal / kg, which included 1 g / kg of protein diet, starting at 08:00 am and ending at midnight. Blood samples were taken at 07:30 am and then at 6:00 pm to measure the level of ammonia and glutamine. Conducted careful monitoring of patients to identify side effects. The drug was well tolerated in each group, and no side effects were observed.

- 12 011716

Table 3

Demographic parameters of patients

Placebo One ornithine One phenylbutyrate Ornithine + phenylbutyrate (PR) Age (P - sick) P1: 47 RH: 46 P5: 56 P7: 52 P2: 57 P4: 40 Рб: 48 P8: 52 Paul (M - man; E - P1: m RH: E P5: E P7: m woman) P2: m P4: E Рб: M P8: g Etiology of the disease P1: note RH: DDP P5: ΝΑ5Η P7: ΗΒν the liver P2: ΗΒν P4: ΝΑ3Η Рб: DDP P8: ΗΒν Severity of the disease P1: 9 RH: 13 P5: 14 P7: 14 liver (scoring RidN) P2: 12 P4: 13 Рб: 13 P8: 12 Accelerating factor P1: infection RH: Gold reserves P5: Gold reserves P7: Gold reserves P2: infection P4: infection P6: infection P8: infection Severity of re (criteria P1: 2 RH: 3 P5: 3 P7. 3 pegs Ηαν <? ΐί) Durability PE (point P1: 9 RH: eight P5: 9 Р7 9 Glasgow Coma Assessment) P2: eight P4: eight Рб: ten Р8 9 Failure P1: not RH: state, ₽5: not Р7 not other organs P2: hypotension previous development of renal failure, hypotension P4: hypotension RB: a condition preceding the development of renal failure Р8 not Dead / alive P1: BUT RH: ϋ P5: BUT Р7 BUT P2: BUT P4: BUT Рб: BUT Р8 BUT Complications ₽1: infection, gold reserves P2: infection, bleeding from esophageal varices RH: NVZ P4: recurrent infection P5: RB: Gold reserves sepsis, yu recurrent P7: no P8: bleeding, 14th day

8BP: spontaneous bacterial peritonitis, non-alcoholic steatohepatitis.

1SI: need support in the intensive care unit.

NK.8: hepatic-renal syndrome.

Results.

FIG. 11 shows that in the placebo group, the average ammonia levels remained largely unchanged during the treatment period. In the group of L-ornithine and phenylbutyrate, the concentration of ammonia increased, compared to the initial values. There was a significant reduction in ammonia levels in the treatment group with bornitine and phenylbutyrate. An increase in ammonia level after a meal was reduced in animals treated with PR, in addition to reducing ammonia concentrations. In both patients in the OR group, the scoring of encephalopathy improved by 2 degrees by the 3rd day, which was not observed in one of the 6 other patients.

FIG. 12 shows that average glutamine levels remained largely unchanged during the treatment period in the OP group, despite a decrease in ammonia levels. There was a decrease in glutamine in the phenylbutyrate group, which can be quite harmful. In the L-ornithine and placebo groups, there was an increase in glutamine concentrations, which increased markedly in the post-meal state.

FIG. 13 shows changes in the mental state in the groups treated with placebo, ornithine (O), phenylbutyrate (P), and PR.

Example 12. The effect of orinitine, phenylbutyrate and isoleucine in patients with hepatic encephalopathy.

Sick.

1. Groups - 2 patients per group. Only 6 patients.

2. Inclusion criteria adult patients aged 18-80 years, liver cirrhosis, documented by histology or clinical criteria, In or С Οΐιίΐά. recent gastrointestinal bleeding from esophageal varices (<6 h after manifestation), informed consent / resolution.

3. Exclusion criteria are another concomitant neurological disorder, the use of another specific drug that reduces the level of ammonia, respiratory failure requiring mechanical ventilation and sedative treatment, profuse gastrointestinal bleeding, hypotension requiring the use of inotropic drugs, obvious renal failure (creatinine> 2 mg / dcl), hemodialysis, extracorporal support of the liver, known hypersensitivity to any of the studied drugs, ber haemorrhage / lactation.

Methods

The open study included 6 patients with cirrhosis who were brought to treat the bleeding of their esophageal varices. They were selected by the severity of the lesion of the liver (see Table 4). They were treated with one of the following regimens for a 3-day period and observations were carried out for 5 days.

The study groups were as follows:

- 13 011716 (ί) Placebo: 5% dextrose for 4 hours (250 ml).

(ίί) One isoleucine: 10 g intravenously in 250 ml of 5% dextrose for 2 hours in two divided doses.

(ίίί) Isoleucine + ornithine + phenylbutyrate: isoleucine: 10 g intravenously in 250 ml of 5% dextrose for 2 hours in two divided doses;

ornithine: 20 g in 250 ml, 5% dextrose (1 = 0, 24, 48 h);

Phenylbutyrate: 10 g 2 times a day, orally (1 = 0, 12, 24, 36, 48 hours).

Patients were hungry during the night from midnight (00:00 h) to 08:00 h in the morning. They were fed intragastric ration 25 kcal / kg, which included 1 g / kg of protein diet, starting at 08:00 am and ending at midnight. Blood samples were taken at 07:30 am and then at 6:00 pm to measure the level of ammonia and glutamine. Conducted careful monitoring of patients to identify side effects. The drug was well tolerated in each group, and no side effects were observed. Due to the fact that patients received sedatives for carrying out their initial endoscopy, it was impossible to interpret the assessment of the mental state. One patient in each of the placebo and isoleucine groups died from multiple organ failure in the hospital. The remaining patients survived.

Table 4

Placebo Ieoleucine alone Ornithine + isoleucine + phenylbutyrate (ΟΙР) Age (P - sick) P1: 43 R2: 62 RH: 57 R4: 42 P5: 43 RB: 45 Paul (M - man; P - P1: M RZ: R P5: M woman) P2: M P4: m RB: M Etiology of liver disease P1: ABO P2: NCS RZ: DDP P4: ABO P5: DDP Рб: ΝΑ3Η Severity of liver disease P1: 13 RZ: 13 P5: 14 (scoring Ridke) P2: 14 P4: 11 RB: 10 Severity NOT (Iez criteria P1: 2 RZ: 2 ₽5: 2 Nauep) R2: 3 P4: 1 RB: 2 Blood loss assessment (u) P1: 9 P2: 10 RZ: 7 R4: 8 P5: 7 RB: 10 Dead / alive P1: ϋ P2: A RZ: A P4: ϋ P5: A RB: A Complications P1: infection, rebleeding P2: severe encephalopathy RH: NKZ P4: recurrent infection P5: chest infection RB: no

8BP: spontaneous bacterial peritonitis.

ΝΆ8Η is not alcoholic steatohepatitis.

1SI: need support in the intensive care unit.

ΗΚ.8: hepatic-renal syndrome.

Results.

FIG. 14 shows that there were no significant changes in ammonia concentrations in the placebo and isoleucine groups. In the group receiving O1P treatment, there was a significant decrease in the concentration of ammonia.

FIG. 15 shows that glutamine levels are not significantly altered by administration of either isoleucine, placebo or O1P. Only in the O1P group there was a significant decrease in the level of ammonia.

FIG. 16 shows that an alternative by which O1P can act is to reduce the level of the ammonia-generating amino acid, glycine. A significant decrease in the level of glycine was observed only in the O1P group.

FIG. Figure 17 shows that isoleucine levels are very low to begin with in each of the groups, but they increase to double the normal values in the groups treated with isoleucine. The concentration in the placebo group remains low and unchanged.

FIG. 18 shows changes in the levels of ornithine in patients during the course of treatment, showing a pronounced, persistent increase in ornithine concentrations, which are significantly reduced to baseline values after cessation of drug administration, indicating seizure in various tissues.

Example 13. The effect of ornithine and phenylbutyrate in rats with a bile duct bandaged. Methods

Induction of liver cirrhosis by bile duct ligation (EBV).

For this procedure male rats of Org-O-Jayu (200-250 g) were used. After anesthesia, laparotomy was performed in the midline, the bile duct was exposed, tied three times with silk thread 4.0 and intersected between the second and third ligature. The wound was sutured in layers of absorbable suture, and the animal was allowed to recover in a calm room before returning to the vivarium. The animals were kept at a constant temperature (20 ° C) with a cycle of light / darkness for 12 hours with unrestricted access to water and standard food for rodents.

5 weeks after EBV (or a false surgery procedure), animals were switched from rodent feed to a completely liquid diet (E1b1, Vu-8egu, Pheisyote N1, ϋδΆ), to which a mixture of amino acids was added, simulating the composition of hemoglobin (2.8 g / kg / day, ΝιιΙπαπ Siuk, Tye # 1 keg1aib8, Probe1

- 14 011716 number 24143). After 6 weeks, under anesthesia, a catheter was inserted into the right carotid artery and used to take repeated blood samples. After this procedure, the initial sample was taken before the administration of the studied formulations by intraperitoneal injection. The study groups were the following: control of VEB + saline (n = 5), VEI + ornithine (0.22 g / kg, n = 6) in saline intraperitoneally, VEI + phenylbutyrate (0.3 g / kg, n = 7 ) in saline solution intraperitoneally, WEI + OR (0.22 g / kg / 0.3 g / kg, n = 7) in saline solution intraperitoneally.

Blood samples were taken in pre-cooled heparinized tubes and stored on ice before processing. Plasma was collected after centrifugation (3000 rpm, 10 min) and stored at -80 ° C before analysis.

The content of ammonia, glucose, lactate and urea was measured using the ROW MPA 3 kit, in accordance with the manufacturer's instructions. The amino acid content was quantified by HPLC with fluorescence detection.

Results.

On the model of cirrhosis due to ligation of the bile duct in rats, there is a significant increase in the level of ammonia in arterial blood plasma (205 ± 11 µmol / l, mean ± 3ЕМ), compared with healthy controls (25.6 ± 2 µmol / l, p < 0.001, data not shown). On this model, the applicants found that in the placebo group treated with saline, there was no change in ammonia levels in arterial blood for 3 hours.

FIG. 19 shows changes in ammonia levels in arterial blood plasma in rats with liver cirrhosis caused by VE, after intraperitoneal injections of saline (control VE, n = 5), ornithine (Ogp, 0.22 g / kg, n = 6), phenylbutyrate ( RV, 0.3 g / kg, n = 7) and ornithine and phenylbutyrate (RR, 0.22 g / kg + 0.3 g / kg, n = 7). * denotes p <0.05 for the OP in comparison with Ogp after 3 h (two-way variational analysis - ΑΝΟνΑ).

This figure shows that in animals treated with ornithine, a slight decrease in the concentration of ammonia was detected, although it was not found to be different from placebo. In the group treated with phenylbutyrate, after 1 h, a significant increase in the plasma ammonia content was found (p <0.01, compared to all other groups), although it was found that this difference was smaller at the time point after 3 hours. These data are consistent with the hypothesis that phenylbutyrate (phenylacetate) is effective only in individuals with increased concentrations of glutamine. In animals without the addition of ornithine, which can be metabolized to form glutamine, the effects of P alone are undesirable and are potentially harmful. A significantly lower level of ammonia was observed in the group treated with ornithine plus phenylbutyrate (RR). In these animals, a prolonged decrease in the level was measured within 3 hours of the study, the levels of which, as was found at the end of the study, were significantly lower than the levels in the group receiving only ornithine (p <0.05).

This clearly shows that the combination of OR is more effective for reducing the plasma ammonia than one O or P. In addition, in animals treated with P alone, increased plasma ammonia levels can have a harmful effect.

In a subset of samples, applicants investigated the capture of ornithine in the blood stream after an intraperitoneal injection of O or RR. FIG. 20 shows the concentration of ornithine in arterial blood in groups with supplements. It is clear that in both groups after intraperitoneal injection, the concentration of ornithine in the plasma increased markedly after 1 h, with a subsequent decrease after 3 h, because ornithine is metabolized in the body. At any time, no significant difference in plasma ornithine concentration was found between these groups.

These data are important because it has been shown that the chosen route of administration is effective in delivering ornithine to these animals. In addition, the rapid uptake and the observed decrease in plasma levels indicate that an active metabolism of this amino acid occurs.

Example 14. The effect of ornithine, phenylbutyrate and isoleucine in rats with a bandaged bile duct.

Methods

Male Zrgadiye-OaMeu rats (200-250 g) were used for this procedure. 48 hrs before killing, animals were transferred from a standard feed for rodents to a completely liquid diet (OdFe, B1oZegu, EghepsN1o \ yn N1, IZA), to which an amino acid mixture was added imitating the composition of hemoglobin (2.8 g / kg, ιιΙπαη Siuk, ТНе №111г1апЙ5. Rgojis! № 24143). Acute hepatic failure (ABU) was induced 24 hours before killing by intraperitoneal injection of galactosamine (1 g / kg, 31 dta, Poole, IR) in saline (n = 5 in each group). 3 hours prior to sacrifice, animals were given either O1P preparative form (0.22 g / kg ornithine, 0.25 g / kg isoleucine, 0.3 g / kg phenylbutyrate in saline intraperitoneally), or saline control. At the end of the experiment, arterial blood was collected in pre-cooled heparinized tubes and stored on ice until processing. Plasma was collected and stored as described above. The ammonia content was determined as above.

- 15 011716

Results.

It was found that ammonia levels in arterial blood were significantly reduced in rats with acute liver failure who received получ, compared to controls that received placebo (Fig. 21). This study was designed to test whether isoleucine in combination with ornithine and phenylbutyrate (phenylacetate) can effectively reduce plasma ammonia levels. It was previously demonstrated that isoleucine alone does not affect ammonia levels in human studies, although its effectiveness in combination with O and P has not been previously tested.

FIG. 21 shows ammonia levels in arterial blood plasma on a model of acute liver failure with elevated levels of ammonia in the blood when treating placebo (saline) (LHP) and ΟΙΡ (LHP + ΟΙΡ). Between these two groups, a level of significance was found for differences p <0.01 (T-test).

These data support the hypothesis that isoleucine, in combination with ornithine and phenylbutyrate, is effective in reducing ammonia levels. This is in addition to the beneficial effects of isoleucine previously described for protein synthesis.

Example 15. The effect of ornithine and phenylbutyrate on the model of devascularization in pigs.

Methods

pigs were randomly divided into 4 groups: acute liver failure (LHP) + placebo + placebo (n = 2); LR + ornithine + placebo; LR + phenylbutyrate + placebo; LR + ornithine and phenylbutyrate. Pigs were injected with catheters in the femoral artery and vein, portal vein, renal vein and pulmonary artery. The experiment was started at time = -1 h, when a placebo or a therapeutic infusion was started.

1. Placebo: 5% dextrose for 3 hours, oral water as a placebo.

2. One ornithine: 0.3 g / kg, 5% dextrose for 3 h intravascular drip.

3. Phenylbutyrate: 0.3 g / kg, 5% dextrose for 3 h intragastric feeding.

Ornithine + phenylbutyrate: 0.3 g / kg, 5% dextrose for 3 h intravascular drip, 0.3 g / kg, 5% dextrose for 3 h intragastric feeding.

LRP was caused by an anastomosis of the portal vein with the inferior vena cava and subsequent ligation of the hepatic artery (devascularization) at time = 0 h, infusion was stopped at time 1 = +2 h, and the experiment was stopped at time = 8 h 0, 1, 3, 5, 7 and 9 h to measure changes in the regional content of ammonia and amino acids. At the end of the experiment, a frontal cortex slice was removed to measure the water content in the brain tissue.

Results.

After the infusion of ornithine, which generates intracellular glutamate, and the intragastric delivery of conjugated phenylacetate, the results indicate a profound change in the overall levels of ammonia and the utilization of glutamine on this catastrophic model of liver failure.

There is a consistent increase in the concentration of ammonia in arterial blood over time from the moment of devascularization in animals treated with placebo (Fig. 22), with some muscle production (Fig. 23) and a large amount of ammonia coming from the intestine (Fig. 24). This animal exhibits the most moderate release of muscle glutamine (Fig. 25) and detectable glutamine uptake in the intestine (Fig. 26).

In the case of animal treatment with one ornithine, the early rise in ammonia level is initially smoothed, but it then rises to the highest level at the end of the experiment (Fig. 22). There is a pure capture of ammonia by the muscles of this animal (FIG. 24) with a comparable amount of glutamine released from the muscles, compared with animals receiving placebo (FIG. 25) with increased capture of glutamine by the intestine (FIG. 26).

One phenylbutyrate also exhibits an initial smoothing of ammonia levels in arterial blood, which quickly increase to levels comparable to one ornithine at the end of the experiment (Fig. 22) with a slight change in the capture of ammonia by the muscles (Fig. 23), but the production of ammonia in the intestine ( Fig. 24). Interestingly, there is a net removal of glutamine by the muscles in the treatment with phenylbutyrate alone (Fig. 25) with a slight clear effect on the uptake of glutamine compared with animals receiving placebo treatment (Fig. 26).

The combination of ornithine and phenylbutyrate has the greatest effect on ammonia levels in arterial blood with a marked decrease in its levels in circulating blood at the end of the experiment, compared with all other animals (Fig. 22). Ammonia is actively removed from the blood by the muscles of this animal (Fig. 23) with significantly reduced production of ammonia in the intestine (Fig. 24). It is interesting to note that the release of glutamine from the muscles is increased, compared to animals treated with placebo and ornithine alone (Fig. 25). Despite this increased muscle glutamine production, the uptake of glutamine in the intestine is significantly reduced (Fig. 26).

Elevated levels of ornithine in circulating blood in animals treated with ornithine are shown in FIG. 27.

Impact of devascularization and therapeutic interventions on glutamine in arterial blood while

- 16 011716 is shown in FIG. 28. There is an increase in the level of glutamine in the circulating blood of an animal treated with ornithine, which is reduced by co-administration of phenylacetate. Interesting data consisted in a significant reduction in the levels of glycine in arterial blood, which were found in an animal treated with ornithine and phenyl butyrate (Fig. 29).

At the end of the experiment, the frontal cortex was removed and the water content in the brain was measured (Fig. 30).

An independent pathologist reported on the cellular anatomy of the brain in these experimental animals. His report is summarized below.

LEE: Microvessels with perivascular edema with surrounding vesicles. A neuron with necrotic changes surrounded by vesicles.

LEE + O + P: Microvessels with perivascular edema with surrounding vesicles (less than as a result of LEE without any treatment). Intracellular edema.

False Intervention: Brain tissue with minimal ultrastructural changes = normal brain tissue.

Findings.

Applicants have found that imitating some of the symptoms of an acute attack associated with chronic liver disease, such as increasing the concentration of ammonia or imitating gastrointestinal bleeding, leads to a decrease in neutrophil function, and this decrease can be partially eliminated by ornithine or isoleucine. Restoration of neutrophil function by both ornithine and isoleucine plays an important role in preventing sepsis, which is a common accelerating factor in the progression of hepatic decompensation.

In addition, applicants have found that isoleucine does not affect the rise in ammonia concentration after simulated gastrointestinal bleeding. Therefore, unlike the hypothesis that ammonia levels will decrease after the introduction of isoleucine due to stimulation of protein synthesis, there is no effect on ammonia levels. Thus, it is particularly preferable to use isoleucine in combination with ornithine, which is known to reduce ammonia levels.

Therefore, the introduction of ornithine and isoleucine prevents the metabolic effects of gastrointestinal bleeding. Increasing ammonia levels are smoothed, isoleucine deficiency is corrected and neutrophil function is restored. Therefore, the combined use of ornithine and isoleucine provides a new way to treat patients after an accelerating event to prevent the occurrence of hepatic decompensation.

The applicants also found that b-ornithine-b-aspartate (b), which is used to reduce the level of ammonia in patients with hepatic encephalopathy, does not eliminate the effect of ammonia on neutrophil function. Thus, the use of one ornithine is more preferable than the use of LP, since ornithine can reduce the ammonia content and preserve the function of neutrophils. The aspartate component BOL also accumulates in the body. This accumulation of aspartate can actually be detrimental to patients, since aspartate exacerbates the effect of ammonia on neutrophil function, causing a further decrease in neutrophil function. Accordingly, preventing or delaying the onset of hepatic decompensation can be achieved using ornithine in combination with isoleucine, preferably in the absence of aspartate.

In addition, the applicants have found that treating patients with hepatic encephalopathy (NOT) ornithine-b-aspartate (GO) reduces ammonia levels and, as a result, increases glutamine levels. However, glutamine is only a temporary ammonia buffer, since it can recycle and regenerate ammonia in the kidneys and small intestine. Consequently, the treatment of BOL can also lead to a secondary rise in ammonia levels, making an additional contribution to the pathology of hepatic encephalopathy.

The use of phenylacetate or phenylbutyrate in children with urea cycle disorders reduces pathologically high levels of glutamine. In contrast, patients who suffer NO do have normal glutamine levels, while, as shown in Example 1, they are treated with BOIL, which decreases ammonia levels, but increases glutamine levels. Therefore, the use of phenylacetate and / or phenylbutyrate allows you to remove glutamine to prevent secondary elevation of ammonia levels in patients with NOT.

Accordingly, improved treatment for hepatic encephalopathy can be achieved by administering ornithine in combination with at least one of phenylacetate and phenyl butyrate, preferably in the absence of aspartate.

Extensive studies by applicants on experimental models, as well as in people with liver cirrhosis, support the view that the main organ that removes ammonia in patients with liver cirrhosis are muscles that convert ammonia to glutamine, a reaction that uses glutamine. In liver failure, the enzyme responsible for this decrease, glutamine synthetase, is induced, and the provision of glutamate would increase ammonia detoxification.

Ornithine, a precursor of glutamate, detoxifies ammonia by transformation into glutamine. However, preliminary studies by applicants have shown that this glutamine recycles and regenerates ammonia. The invention provides a new method not only to detoxify ammonia into glutamine, but also to eliminate the excess of generated glutamine. Thus, the PR decreases the ammonia concentration.

- 17 011716 ka in patients with cirrhosis of the liver, and an elevated ammonia content in the blood is significantly more pronounced than each individually. This effect is distinctly synergistic, not additive. In addition, an increase in ammonia level after a meal is eliminated by the administration of an OR. This may allow feeding patients with decompensated liver cirrhosis with protein-rich diets without the risk of elevated blood ammonia. A decrease in ammonia was associated with an improvement in mental state. It achieves a reduction in ammonia concentration by preventing an increase in glutamine levels. This is consistent with the hypothesis that ornithine stimulates the production of ornithine in muscles (by capturing, by this, 1 ammonia molecule), but this glutamine is released (possibly as an adduct of phenylacetate), preventing the rise in systemic glutamine, thereby preventing reactive elevated ammonia in blood.

The established fact that phenylacetate reduces ammonia levels in young children with elevated levels of ammonia in the blood with manifestations of urea cycle disorders is that ammonia is captured in glutamine, and that glutamine is transported to the kidneys for excretion of phenylacetate glutamine as an adduct. These young children show a high level of ammonia and, importantly, a high level of glutamine. In contrast, a patient with a cirrhotic condition manifests a high level of ammonia and a glutamine level from normal to low. In the model described above, pigs with cirrhosis do not have an elevated glutamine level, and ammonia levels increase dramatically after liver isolation.

Treatment with ornithine alone causes an increase in blood glutamine levels, while there is no effect on ammonia levels. Phenylbutyrate alone causes a borderline increase in glutamine and again has insignificant effects on ammonia levels. In stark contrast to this, on this catastrophic model of an increasing level of ammonia in the blood, the combination of ornithine and phenibutyrate (PR) causes a detectable decrease in circulating ammonia and reduces the increase in glutamine observed with the introduction of one ornithine. The level of amino acid-generating glycine increased in all animals, however, an increase in the level of this amino acid was significantly smoothed only in an animal treated with PR, indicating the additional benefit of this form of intervention. The established consequence of elevated ammonia is brain edema, as the water content in the brain increases. In the brain of a pig treated with one ornithine, there is a significant increase in water content, although the combined treatment with ornithine and phenyl butyrate reduces the water content in the brain. Histologically, there is less pronounced damage to the microstructure of the brain in an animal that received the combined treatment with ornithine and phenylbutyrate, compared to the animal that received placebo treatment.

Claims (21)

1. The use of ornithine for the manufacture of a medicament for use in combination with at least one of phenylacetate and phenylbutyrate for the prevention or treatment of hepatic decompensation or hepatic encephalopathy. 2. The use of at least one of phenylacetate and phenylbutyrate in the manufacture of a medicament for use in combination with ornithine for the prevention or treatment of hepatic decompensation or hepatic encephalopathy. 3. The use of ornithine and at least one of phenylacetate and phenylbutyrate for the manufacture of a medicament for the prevention or treatment of hepatic decompensation or hepatic encephalopathy. 4. The use according to any one of the preceding paragraphs, wherein the patient with chronic liver disease suffers from indicated hepatic decompensation. 5. The use according to any one of the preceding paragraphs, wherein said prophylaxis or treatment includes delaying the onset of hepatic decompensation. 6. The use according to any one of the preceding paragraphs, where the patient had or, apparently, had in the past an event accelerating the development of hepatic decompensation. 7. The use of claim 6, wherein said accelerating event is gastrointestinal bleeding, infection, portal vein thrombosis, or dehydration. 8. The use according to claim 6 or 7, where the drug is administered within 6 hours after the detection of the symptom (symptoms) of the specified accelerating event or suspected accelerating event. 9. The use according to any one of the preceding paragraphs, where the treatment of hepatic encephalopathy occurs in a patient with chronic liver disease or acute liver failure. 10. The use according to any one of the preceding paragraphs, wherein said ornithine is present as a free monomeric amino acid or physiologically acceptable salt. 11. The use according to any one of the preceding paragraphs, where at least one of phenylacetate and phenylbutyrate is present in the form of sodium phenylacetate or sodium phenylbutyrate. 12. The use according to any one of the preceding paragraphs, where the specified medicinal product further includes isoleucine. - 18 011716 13. The use of claim 12, wherein said isoleucine is present in the form of a free monomeric amino acid or physiologically acceptable salt. 14. The use according to any one of the preceding paragraphs, where the specified medicinal product essentially does not contain another amino acid. 15. The use according to any one of the preceding paragraphs, where the drug is formulated for intravenous, intraperitoneal, intragastric, intravascular or oral administration. 16. A product containing ornithine and at least one of phenylacetate and phenylbutyrate in the form of a combined preparation for simultaneous, separate or sequential use for the prevention or treatment of hepatic decompensation or hepatic encephalopathy. 17. The product according to clause 16, which further includes isoleucine. 18. The product according to clause 16 or 17, which essentially does not include another amino acid. 19. A pharmaceutical composition comprising ornithine and at least one of phenylacetate and phenylbutyrate. 20. The pharmaceutical composition according to claim 19, which further comprises isoleucine. 21. The pharmaceutical composition according to claim 19 or 20, which essentially does not include another amino acid.